Half-life extended biotherapeutics

ABSTRACT

Introduction: Many of the biotherapeutics approved or under development suffer from a short half-life necessitating frequent applications in order to maintain a therapeutic concentration over an extended period of time. The implementation of half-life extension strategies allows the generation of long-lasting therapeutics with improved pharmacokinetic and pharmacodynamic properties.

Areas covered: This review gives an overview of the different half-life extension strategies developed over the past years and their application to generate next-generation biotherapeutics. It focuses on srategies already used in approved drugs and drugs that are in clinical development. These strategies include those aimed at increasing the hydrodynamic radius of the biotherapeutic and strategies which further implement recycling by the neonatal Fc receptor (FcRn).

Expert opinion: Half-life extension strategies have become an integral part of development for many biotherapeutics. A diverse set of these strategies is available for the fine-tuning of half-life and adaption to the intended treatment modality and disease. Currently, half-life extension is dominated by strategies utilizing albumin binding or fusion, fusion to an immunoglobulin Fc region and PEGylation. However, a variety of alternative strategies, such as fusion of flexible polypeptide chains as PEG mimetic substitute, have reached advanced stages and offer further alternatives for half-life extension.

KEYWORDS:

• Albumin
• glycosylation
• Fc region
• FcRn
• fusion protein
• half-life extension
• PEGylation
• polymer

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Corrigendum

Article highlights

• Many of the biotherapeutics being approved or under development suffer from a short serum half-life. Half-life extension has been recognized as an approach to facilitate application of biotherapeutics and ease a patient’s burden by increasing the time between applications.

• Half-life extension strategies primarily aim at increasing the size and, thus, hydrodynamic volume of the biotherapeutic, e.g. by conjugation of polymers, fusion of recombinant polymer mimetics, introduction of glycosylation sites, and fusion to plasma proteins.

• Some of the half-life extension strategies such as fusion to an Fc region or fusion or binding to serum albumin also implement recycling by the neonatal Fc receptor, which can further extend the half-life.

• Several half-life extension strategies allow for a fine-tuning of half-life, e.g. by adapting the composition or length of added chemical or recombinant polymers.

• A plentitude of half-life extension strategies is available and different approaches are already utilized in approved biotherapeutics, with many more half-life extended biotherapeutics being in preclinical and clinical development.

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Declaration of interest

R Kontermann is an employee of the University of Stuttgart and a named investor on a number of patents assigned to the University of Stuttgart in the subject field of this review. He is a consultant for various companies and firms related to the topic of half-life extension receiving honoraria for expert testimony and consultancy. He has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.